The present invention provides an improved process for the preparation of 3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propylamine (I). ##STR1##
The present invention also provides intermediates useful in the disclosed process.
The synthesis of compound (I) has previously been disclosed in U.S. Pat. No. 6,048,861 (Apr. 11, 2000); U.S. Pat. No. 5,952,341 (Sep. 14, 1999); WO 98/18460; and WO 99/31061. In these references, the naphthyridine ring is constructed by way of a Friedlander reaction between 2-amino-3-formyl-pyridine and 2-oxo-5-(benzyloxycarbonylamino)-pentane or 2-oxo-5-(t-butyloxycarbonylamino)-pentane. The described procedures involve a total of seven chemical transformations, several chromatographic purifications, and an overall yield of about 38%.
In the present invention, compound (I) is produced highly efficiently in a total of three chemical steps from a protected allylamine with an improved overall yield of about 76%. The method features a one-pot double Suzuki cross-coupling of a 2,5-dihalopyridine with a protected allylamine, deprotection, and a highly regioselective intramolecular Chichibabin-type cyclization to afford the final product (I).